Acute renal failure is defined as having symptoms of azotemia, electrolyte imbalance, uremia and the like caused by acute renal dysfunction. Acute renal failure is classified into prerenal acute renal failure, renal acute renal failure and postrenal acute renal failure caused by renal dysfunction. Renal acute renal failure is classified into (1) vasculitis, glomerular lesion, (2) acute interstitial nephritis, (3) tubule obstruction and (4) acute renal failure in a narrow sense. Acute renal failure in a narrow sense is caused by acute tubular necrosis. The acute renal failure in a narrow sense results from (1) ischemia, (2) nephrotoxic substance, or (3) myolytic substance (e.g. myoglobin) and so on.
Ischemic acute renal failure is caused by bleeding from surgery, shock, external injury, burn and the like. Experimental animal model for ischemic acute renal failure is exemplified by renal artery ligation. In the rat model, BUN (blood urea nitrogen) and serum creatinine are increased, HGF (Hepatocyte Growth Factor) mRNA expression is enhanced 6 to 12 hours after ischemia, and then HGF bioactivity in rat kidney and plasma is activated (American Journal of Physiology, 1993; 265; 61-69).
Acute renal failure is also caused by a nephrotoxic substance such as anti-biotic agent, antitumor agent, contrast medium. An experimental animal model of acute renal failure caused by a nephrotoxic substance is made by administration of a compound such as mercurous chloride, cisplatin, and contrast medium to rats. Mercurous chloride administered rats show an increase of BUN and creatinine, enhancement of HGF mRNA expression and activity of HGF (Nephron 1996; 73: 735), as reported on ischemia model. It is suggested that HGF be involved in restoring a patient from renal failure.
It is reported that renal dysfunction in experimental animal models caused by ischemia or a nephrotoxic substance such as mercurous chloride and cisplatin is recoverable by HGF administration (American Journal of Physiology, 1994; 266; 129-134, Proc. Natl. Acad. Sci. 1994; 91; 4537-4361). In both models, the increase of BUN and creatinine is recovered rapidly by HGF administration. It is considered that HGF acts as a renotropic factor to enhance proliferation of damaged tubular cells.
Myolytic substances (such as myoglobin, phosphate, potassium, and uric acid) are released by external injury, compression damage (e.g. crash syndrome), burn, infection, drug poisoning (e.g. alcohol, barbitur derivatives), muscle metabolic disease, overuse of muscle, hypophosphatemia, snake venom and the like and show toxicity to tubular cells. As a result, necrosis of tubular cells occurs, and necrotic cells and protein (hyaline) casts bring tubular obstruction. It is also reported that myoglobin reduces renal blood flow. The above mentioned mechanism is considered to cause acute renal failure caused by rhabdomyolysis (Common Disease Series 17: Zinfuzen (renal failure), 57-61, Nankoudo, (1991)).
Clinical symptoms of rhabdomyolysis are: (1) increase in muscle derived enzyme such as creatine phosphate kinase, lactate dehydrogenase, aldolase, glutamic-oxaloacetic transaminase: (2) enhanced uptake of 99 mTC-pyrophosphate into injured muscle; (3) presence of myoglobin; (4) BUN/serum creatinine ratio of 10-20 or under; (5) hyperuricemia; and (6) hyperphosphatemia, hypocalcemia and hyperpotassemia.
The methods of treatment for rhabdomyolisis include fluid replacement therapy, administering diuretics, fascia release therapy, plasmapheresis, antiplatelet therapy, but these methods of treatment are not adequate for a severe or poor prognosis. There is no adequate method of treating or preventing acute renal failure caused by rhabdomyolysis or pharmaceutical composition for treating or preventing acute renal failure caused by rhabdomyolysis.
There is also no adequate method of treating or preventing hemolytic uremic syndrome (HUS) or a pharmaceutical composition for treating or preventing HUS. Clinical characterization of HUS is thrombocytopenia, microangiopathic hemolytic anemia, and symptoms of acute renal failure. The cause of HUS are infection (e.g. O157), hereditary, administration of drug (e.g. cyclosporin), pregnancy, organ graft, SLE, hypertension, different group blood transfusion and the like. Hemolysis is caused by the above conditions, and then hemoglobin and the like are released, and HUS occurs as a result.
A glycerol-induced animal model is well known for use in modeling acute renal failure. When glycerol is injected into the muscle of animals, hyperosmolarity of glycerol causes hemolysis in muscle cells and intramuscular vessel in the animal model. Myoglobin, hemoglobin, potassium and other rhabdomyolytic substances are released into the blood and damage renal cells. Dehydration in the animal model further enhances the toxicity of the rhabdomyolytic substances. As a result severe decrease of renal blood flow and ischemia are caused, and severe glomerular filtration causes oliguresia and anuria. The part of muscle where glycerol is administered becomes a place to store bodily fluid, and systemic circulation, blood flow rate, and cardiac output are reduced (JINSIKKAN MODEL (a model for renal disease), JIN TO TOUSEKI (kidney and dialysis) Vol. 31 (1991) 395-399). If the model animal is deprived of water before the administration of glycerol, the effect of myolytic substances is enhanced and rhabdomyolytic model is induced.
The present invention provides a pharmaceutical composition for treating acute renal failure caused by rhabdomyolysis comprising a therapeutically effective amount of HGF.
The present invention provides a method of treating acute renal failure caused by rhabdomyolysis comprising administering a therapeutically effective amount of HGF to a patient, particularly a human patient, in need thereof.
The present invention further provides a pharmaceutical composition for treating myoglobinuria comprising a therapeutically effective amount of HGF.
The present invention further provides a method of treating acute renal failure caused by rhabdomyolysis caused by a myolytic substance released by external injury, compression damage (e.g. crash syndrome), burn, infection, drug poisoning (e.g. alcohol, barbitur derivative), muscle metabolic disease, overuse of muscle, hypophosphatemia, snake venom and the like comprising administering a therapeutically effective amount of HGF to a patient in need thereof.
The present invention further provides a pharmaceutical composition for treating acute renal failure caused by rhabdomyolysis caused by a myolytic substance released by external injury, compression damage (e.g. crash syndrome), burn, infection, drug poisoning (e.g. alcohol, barbitur derivative), muscle metabolic disease, overuse of muscle, hypophosphatemia, snake venom and the like comprising a therapeutically effective amount of HGF.
The present invention further provides a pharmaceutical composition for treating hemolytic uremic syndrome comprising a therapeutically effective amount of HGF and a pharmaceutically acceptable carrier.
The present invention further provides a method of treating hemolytic uremic syndrome comprising administering a therapeutically effective amount of HGF to a patient in need thereof.
The present invention further provides a pharmaceutical composition for treating hemolytic uremic syndrome caused by infection (O157), heredity, administration of drug (cyclosporin), pregnancy, organ graft, SLE, hypertension, different group blood transfusion and the like comprising a therapeutically effective amount of HGF and a pharmaceutically acceptable carrier.
The present invention further provides a method of treating hemolytic uremic syndrome caused by infection (e.g. O157), heredity, administration of drug (e.g. cyclosporin), pregnancy, organ graft, SLE, hypertension, different group blood transfusion and the like comprising administering a therapeutically effective amount of HGF to a patient in need thereof.